Mastocytosis is a heterogeneous disorder characterized by clonal
proliferation and accumulation of mast cells in one of more organs which
may lead to different clinical pictures. Pathological increase and
activation of mast cells in various tissues can cause different clinical
pictures. Cutaneous mastocytosis limited to the skin is the most typical
clinical picture observed in children and systemic mastocytosis is very
rare in the pediatric age group. The diagnosis of cutaneous mastocytosis
is based on clinical findings, but is often delayed due to lack of
clinical awareness of the disease and lack of its consideration in the
differential diagnosis. This article focuses on the current diagnosis,
management and treatment of cutaneous mastocytosis in children in order
to increase awareness about this issue.

(Turk Pediatri Ars 2016; 51: 123-7)

Keywords: Child, cutaneous, mastocytosis

Introduction

Mastocytosis is a disorder characterized by clonal proliferation
and accumulation of mast cells in one or more organs which may lead to
different clinical pictures (1). It may be in the form of cutaneous
mastocytosis with involvement of the skin alone or systemic mastocytosis
with involvement of multiple organs.

Mastocytosis is defined in two main ways: cutaneous mastocyutosis
characterized with cutaneous involvement and systemic mastocytosis
characterized with involvement of the organs including liver, spleen,
lymph nodes and/or bone marrow. However, a new classification was made
by the World Health Organization in 2008 (Table 1) (2, 3).

Mastocytosis may be observed in all ethnic groups and age groups.
In children, it is typically observed in the form of cutaneous
mastocytosis and systemic mastocytosis is substantially rare (4). In
adults, it is generally characterized with more serious systemic
findings.

Pathogenesis

Mast cells are found in the skin and many tissues and lead to
various clinical symptoms and signs by secreting many mediators when
they are induced. The mediators secreted from the mast cells and their
roles are shown in Table 2 (5). Abnormal accumulation of mast cells in
tissues and the mediators they secrete are involved in the pathogenesis
of mastocytosis. Both uncontrolled proliferation and defective
apopytosis are responsible of accumulation of mast cells in tissues (6).

Mast cells originate from hematopoetic progenitor cells. Mast cell
progenitors have been demonstrated in the bone marrow and peripheral
blood (7, 8). It is thought that these cells migrate and differentiate
and mature in various organs (9). The most important one among growth
factors is "stem cell factor (SCF)". This factor is also named
mast cell growth factor or KIT ligand. Mast cells develop from CD34+
progenitor cells by way of stem cell factor (10, 11). The effects of
stem cell factor on mast cells and mast cell progenitors is mediated by
KIT which is encoded by c-kit protooncogene and is a tyrosine kinase
receptor for SCF (12). Stem cell factor and SCF-related KIT activation
are essential for development and differentiation of mast cells.
"Activating" mutations located in the kinaze region of the KIT
protein lead to excessive development of mast cells and their
progenitors (13). Among these mutations which lead to transformation of
cells, Asp-816-Val mutation is observed commonly especially in adult
patients with systemic mastocytosis (14-16).

Cutaneous mastocytosis

Cutaneous mastocytosis was reported in 1936 for the firts time by
Sezary and Chauvillon (17). Although there is no clear data about the
prevalence of cutaneous mastocytosis, it was reported to be 1/500 in
children presenting to pediatric dermatology cinics in one study (18).
It is clinically manifested as urticaria pigmentosa, diffuse cutaneous
mastocytosis or solitary mastocytosis (2).

Urticaria pigmentosa is the most common form. It is generally
manifested as a stable, red-brown lesions in the form of maculopapular
plaque, nodule or bulla in any region of the body, scalp, face trunk and
extremities in infancy (19). Pruritus of varying degrees accompanies the
lesions (20). In cutaneous lesions, erythema and urticaria may develop
around the lesion with physical trauma including rubbing and friction;
this is called "Darier's sign" (21). Sudden blushing may
develop in the lesions with hot bath, cold water or exercise (22). On
histopathological examination of the cutaneous lesions, mast cell
accumulation is observed along the papillary dermis and reticular dermis
and inside the subcutaneous adipose tissue (23). Therefore, the
incidence of atopic disease is increased compared to the general
population (24).

Diffuse cutaneous mastocytosis is a rare type of mastocytosis which
occurs in childhood. It is usually observed in adults. Lesions in the
form of diffuse xanthogranulomas similar to yellow-orange subcutaneous
nodules or diffuse red bullae are observed (19). Dermatographism mostly
result in hemorrhagic bullae. Urticaria pigmentosa has a more severe
course and may lead to life-threatening conditions by causing
hypovolemic shock, mast cell leukemia, gastrointestinal hemorrhage and
cachexy (25). Mast cell infiltration is observed around the blood
vessels along the whole dermis (23).

Single or multiple brown nodules are observed in solitary
mastocytoma. If these nodules are exposed to any trauma including
friction, they may lead to xing and systemic symptoms including
hypotension. Histologically, mast cell infiltration which shows
extensions into the papillary and reticular dermis is observed in the
subcutaneous tissue without cytological atypia (23).

Diagnosis

The diagnosis of cutaneous mastocytosis is made clinically and
confrmed histopathologically. On histopathological examination of the
cutaneous lesions, mast cell accumulation is found and the mast cells
are differentiated by metachromatic staining by Giemssa and Toluidine
dyes (26). SCORMA (SCORing MAstocytosis index) and serum triptase level
should be evaluated in all pediatric patients with mastocytosis (27).
The SCORMA index is a scoring system which is used in specifying the
disease severity (Figure 1) (28). The flowchart which should be followed
when there is a suspicion of mastocytosis is presented in Figure 2 (19).

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Generally, bone marrow aspiration and biopsy are not recommended in
children aged below 5 years with acute-onset cutaneous mastocytosis.
However, it is beneficial to perform bone marrow aspiration and biopsy,
if additional conditions including abnormal complete blood count,
hepatosplenomegaly and lymphadenopathy are present. Bone marrow biopsy
should be absolutely performed, if systemic mastocytosis is considered.
Evaluation of bone marrow aspiration by way of flow-cytometry is
diagnostic.

The diagnostic criteria for systemic mastocytosis specified by the
World Health Organization in 2008 are presented in Table 3 (2).

Treatment

Generally, treatment is not needed in patients with isolated
cutaneous mastocytosis. Patients and families should be informed that
they should avoid excessively hot bath, sudden temperature changes,
physical stimulation, hardly rubbing of the skin, stress, bee bite and
drugs including aspirin, codeine, morphine, alcohol and radiocontrast
substances containing iodide to prevent exacerbations (23). Education
related with use of epinephrine autoinjector in case of sudden
hypotension which is observed as a result of acute degranulation of mast
cells should be given. In this case, corticosteroid and antihistaminic
treatment may be administered additionally.

In children aged above 2 years, topical therapies may be given, if
cosmetic problems are present. Closed dressing may be preferred, if the
lesions cover 10% of the body. However, topical corticosteroid creams
should be preferred, if the lesions cover more thanl0% of the body (29).
One should be cautious in terms of secondary bacterial infections while
using these creams. If pruritus, erythema and swelling occur, systemic
H1 and H2 antihistaminics and cromolyn sodium may be helpful (29).

Treatment is controversial in diffuse cutaneous mastocytosis. If
frequent hospitalization is required or life-threatenting reactions are
observed, imatinib treatment may be tried. Imatinib mesilate is a type 2
kinase inhibitor. It induces cell growth and apopytosis by binding to
adenosine 3 phosphate and the adjacent kinase domain. It may lead to
cardiomyopathy and stunted growth in children. Other side effects
include nausea, vomiting, diarrhea, increased liver enzymes,
hypophosphatemia, edema, rush, granulocytopenia, anemia and
thrombocytopenia. However, these side effects are observed rarely in
children. The initial dose in children is 200 mg/[m.sup.2]/day. One
should taper the dose to the dose which is sufficient to control the
cutaneous lesions as soon as possible. Complete blood count, liver
enzyme tests and growth rate should be absolutely checked (25).